HIV is the etiologic agent of AIDS, an immunodeficiency disease with multi-organ involvement. The mechanism by which HIV causes the wide spectrum of disease and in particular, the CNS disease manifested as the AIDS dementia complex is an enigma. SIV, a lentivirus isolated from macaques, is related to HIV-1 and more closely to HIV-2, a virus associated with AIDS in West Africa. The simian virus causes a disease like AIDS in humans, including opportunistic infections and involvement of multiple organ systems. Further, SIV infects T4 lymphocytes and monocyte/macrohages. With these parallels SIV provides an animal model to investigate the pathogenesis of AIDS and the molecular mechanisms by which these viruses cause their complex disease. The genomes of individual isolates of HIV as well as other lentiviruses display substantial nucleotide sequence heterogeneity, particularly in the envelope gene. Whether this herterogeneity plays a role in persistent infection and cell tropism is not known. Primary HIV isolates generally have distinct tropisms for T4 lymphocytes or macrophages. The macrophage tropic viruses have been implicated in the neurologic disease because the macrophage is the major infected cell in lesions of the AIDS dementia complex. The aim of this project is to examine the changes that occur in the SIV viral genome during adaptation to different cells and under immune selective pressures. To identify the genetic determinants of cell tropism, the lymphocyte tropic SIV will be adapted to grow in macrophage cultures and the genetic changes that accompany adaptation will be determined. In addition, we will identify the genetic determinants of neurotropism. SIV virus will be neuroadapted by serial passage in brain. The genomic changes which accompany this alteration in tropism will be determined. Antigenic variation has been demonstrated for HIV in vitro and HIV isolates from infected individuals show genetic heterogenity in their env gene. Analysis of antigenically distinct viral isolates from persistently infected monkeys will enable us to characterize the epitopes of the SIV env gene which undergoes mutation and antigenic selection. The neutralizing specificities of antibodies to the parental and variant epitope will be examined to determine whether the selective pressure exerted by antibody resulted in the emergence of the variant virus. These studies should enable us to determine the molecular basis of SIV cell tropism for the macrophage, its role in the CNS disease and the role of antigenic variation in viral persistence.